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Cardiac ion channel safety profiling on the IonWorks Quattro™ Automated Patch Clamp System

Cao, Xueying and Lee, Yan and Holmqvist, Mats and lin, Yingxin and Ni, Yucheng and Mikhailov, Dmitri and Zhang, Haiyan and Hogan, Christopher and Zhou, Liping and Lu, Qiang and Digan, Mary and Urban, Laszlo and Erdemli, Gul (2010) Cardiac ion channel safety profiling on the IonWorks Quattro™ Automated Patch Clamp System. Assay and drug development technologies.

Abstract

The normal electrophysiologic behavior of the heart is determined by the integrated activity of specific cardiac ionic currents. Mutations in genes, whose expression results in the molecular components of individual cardiac ion currents have been shown to result in multiple cardiac arrhythmia syndromes. Presently 12 genes associated with inherited LQTS have been identified and the most common mutations are in the hKCNQ1 (LQT1, Jervell and Lange-Nielson syndrome), hKCNH2 (LQT2) and hSCN5A (LQT3, Brugada syndrome) genes. Several drugs have been withdrawn from the market or received black box labeling due to clinical cases of QT interval prolongation, ventricular arrhythmias and sudden death. Other drugs have been denied regulatory approval due to their potential for QT interval prolongation. Furthermore, off-target activity of drugs on cardiac ion channels has been shown to be associated with increased mortality in patients with underlying cardiovascular diseases. Since clinical arrhythmia risk is a major cause for compound termination, preclinical profiling for off-target cardiac ion channel interactions early in the drug discovery process has become common practice in the pharmaceutical industry.
In the present study, we report assay development for three cardiac ion channels (hKCNQ1/minK, hCav1.2 and hNav1.5) on the IonWorks Quattro™ system. We demonstrate that these assays can be used as reliable pharmacological profiling tools for cardiac ion channel inhibition to assess compounds for cardiac liability during drug discovery.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/3597

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